Pain occurring as a consequence of vasocclusive events is the most frequent complaint leading to hospitalization of patients with sickle cell disease (SCD). To date, basic studies have focused on the role of red cell sickling and on the interactions of erythrocytes with endothelium in the initiation and propagation of vascular occlusion. Attention now is turning towards the role of other blood cells, e.g. platelets and neutrophils, and on activation of the coagulation system in the pathophysiology of vasoocclusion. Although activation of the complement system in patients with sickle cell anemia has been reported by a number of investigators, the role of complement activations has been completely ignored in basic studies on the pathogenesis of vasoocclusion. The potential importance of complement in this process is underscored by studies demonstrating the ability of complement activation to increase expression of several different endothelial adhesion molecules and to increase expression of tissue factor on both monocytes and endothelial cells. Recent data have shown that loss of normal cell membrane phospholipid asymmetry resulting in the accumulation of phosphatidylserine (PS) in the outer membrane leaflet causes both erythrocytes and activated platelets to become activators of the alternative pathway of complement, resulting in the deposition of C3b on the membranes of these cells. These findings are relevant to SCD because both activated platelets and a subset of erythrocytes that express PS have been found circulating in the blood of patients with sickle cell anemia. Based on these findings, the hypothesis that complement activation could play a vital role in the pathophysiology of vasoocclusion in patients with SCD will be examined. The aims of the research are as follows. First, to examine the effect of complement activation on endothelial cell expression of adhesion molecules and tissue factor using PS-expressing cells generated in vitro or PS-expressing cells from patients with sickle cell disease to activate complement. Second, to characterize the role of C3b deposition on PS-expressing cells on cell-to- cell adhesion as it relates to the formation of cellular aggregates and the level of tissue factor expression by peripheral blood monocytes. Third, to examine cells isolated from the peripheral blood of SCD patients for the presence of complement activation products and to define the factors that influence the deposition of these molecules on the cells. The results of these studies should provide important new insights into the pathogenesis of vasoocclusion and the potential use of pharmacologic complement blockade in its treatment.